<p>Candesartan (CDN) is a potent antagonist of the angiotensin II receptor known for its protective effects against cardiotoxicity. However, the oral administration of CDN exhibits limited therapeutic effectiveness due to factors such as first-pass hepatic metabolism, low solubility, and low bioavailability. This study's primary objective was to improve the cardioprotective efficacy of CDN in mitigating cardiotoxicity by developing a nasal in situ pH-sensitive formulation of CDN-loaded transbilosomes (ISPCLT). The Box-Behnken design was used to identify the optimal CDN-loaded transbilosome (CLT) formulation. The ISPCLT formulation was then developed by mixing the optimal CLT formulation with a mixture of chitosan and glyceryl monooleate. The bioavailability and efficacy of the ISPCLT formulation were examined in a cardiotoxicity rat model. The optimal CLT formulation consists of 262.6 mg of phospholipid, 20.4 mg of Span 60, and 10.2 mg of sodium deoxycholate. The ISPCLT formulation demonstrated a 2.55-fold increase in CDN release, a 7.04-fold increase in CDN permeation, and a 5.13-fold increase in CDN bioavailability compared to the free CDN suspension. The nasal ISPCLT formulation resulted in a 62.14% increase in body weight, a 95.98% decrease in lactate dehydrogenase levels, and a 93.39% reduction in CK-MB isoenzyme-MB levels when compared to the oral CDN suspension. Histopathological examination validated the ISPCLT formulation's cardioprotective action. The nasal ISPCLT formulation enhances patient adherence and minimizes the risk of adverse effects by allowing for lower dosages. The findings suggest that new strategies for managing cardiotoxicity may be viable with the nasal ISPCLT formulation.</p> Graphical Abstract <p></p>